Psychiatrists, neuropsychiatrists, primary care physicians, nurse practitioners, psychologists, psychiatric nurses, social workers and other mental health care professionals. Continuing education credit is available for most specialties. To determine if this article meets the requirements of your specialty, please contact your state licensing board.

Dr. Mackin is Academic Specialist Registrar in the department of psychiatry at the University of Newcastle upon Tyne, U.K. He has indicated that he has nothing to disclose.

Dr. Young teaches adult psychiatry at the University of Newcastle upon Tyne, U.K. He has a special interest in mood disorders and has published widely in the field of neuropsychopharmacology. He has indicated that he has nothing to disclose.

Mood disorders are leading causes of both morbidity and mortality. Depressive disorder and bipolar disorder (BD) rank among the leading causes of disability worldwide (Murray and Lopez, 1997). Traditionally, mood disorders were considered to be relapsing and remitting conditions characterized by complete inter-episode recovery, but recent evidence has suggested that even during periods of euthymia, neurocognitive impairments known to be present during mood episodes may still persist (Ferrier and Thompson, 2002).

Both Kraepelin (1896) and Freud (1905) regarded endocrinology as potentially important in the causation and treatment of major psychiatric disorders, and the role of dysfunctional endocrine systems in the pathogenesis of mood disorders has been the focus of research for many decades. Poor understanding of the complexity of endocrine systems and their interaction with neural networks, combined with primitive methodology, frustrated early attempts to establish links between endocrine dysfunction and mood disorders (Michael and Gibbons, 1963). More recently, developments in the field of neuroendocrinology have highlighted the significance of endocrine systems in the etiology and pathogenesis of mood disorders.

Despite considerable advances in the treatment of mood disorders during previous decades, there remains an urgent need to identify compounds that will successfully treat mood episodes (including the associated neurocognitive impairments) and prevent their recurrence. This article reviews some of these recent developments, with an emphasis on the role of cortisol in relation to depression.

Glucocorticoids

Glucocorticoids are the end product of the hypothalamic-pituitary-adrenal (HPA) axis and are central to the stress response. There is overwhelming evidence that during periods of acute stress, glucocorticoids promote survival by mobilizing energy reserves. In addition to these short-term adaptive changes, glucocorticoids are also involved in other longer-term, stress-related adaptive changes such as shaping and regulating a number of physiological processes,
including immune responsiveness and activation of the sympathetic nervous
system. Although glucocorticoid production is essential for survival,
overproduction is associated with a significant disruption of cellular
functioning, which, in turn, leads to widespread physiological dysfunction.

The HPA Axis

Cortisol, a glucocorticoid released from the adrenal cortex, is the end
product of the HPA axis. The HPA axis comprises the tissues of the hypothalamus,
pituitary and adrenal cortices; regulatory neuronal inputs; and a variety of
releasing factors and hormones (Figure 1). A variety of stressors, both physical
and psychological, cause the neurosecretory cells within the paraventricular
nucleus of the hypothalamus to secrete corticotropin-releasing hormone (CRH) and
arginine vasopressin (AVP) into the microportal circulatory system of the
pituitary stalk. These secretions cause the release of adrenocorticotropic
hormone (ACTH) from the anterior lobe of the pituitary. Cortisol is released
from the adrenal cortex in response to ACTH. Cortisol has a panoply of central
and peripheral effects that are mediated via at least two intracellular
specialized glucocorticoid receptor subtypes: the high-affinity type I receptor
(or MR) and the low-affinity type II receptor (or GR). In the resting state,
these receptors exist in the cytosol, stabilized by a variety of proteins.
Glucocorticoids readily diffuse through the cellular membrane and bind to these
receptors, which promotes their translocation to the nucleus. Within the
nucleus, the activated receptors interact with other transcription factors or
bind to specific DNA, thus promoting the expression of various genes.

The activity of the HPA axis is highly regulated. Secretory cells within the
paraventricular nucleus receive neuronal inputs from a number of brain regions
including the amygdala, hippocampus and nuclei within the midbrain (Figure 2).
The HPA axis also has an autoregulatory mechanism mediated by cortisol.
Endogenous cortisol binds to glucocorticoid receptors in the HPA axis tissues
and hippocampus and acts as a potent negative regulator of HPA activity. The
relative contribution of the two receptor subtypes (GR and MR) in the regulation
of HPA activity is as yet unclear. The MRs have a high affinity for endogenous
glucocorticoids such as cortisol, as well as for the salt-regulating hormone
aldosterone. However, the GRs have a relatively low affinity for cortisol, but
bind avidly to synthetic steroids such as dexamethasone. These differences in
affinity suggest that MRs play a primary role in regulating basal cortisol
levels when hormone levels are low. When cortisol levels rise, as from stress or
circadian fluctuations, the MRs become saturated, and GRs become the main
transducers of glucocorticoid activity and therefore the primary mediators of
HPA feedback. These regulatory mechanisms are important in determining basal
levels and circadian fluctuations in cortisol levels. Changes in GR number or
function may be important in altering the homeostatic function of the HPA axis
observed in healthy individuals.

Cortisol and GR Abnormalities

The first observations of abnormalities of cortisol levels in patients with
depression were made in the late 1950s by Board and colleagues (Michael and
Gibbons, 1963), and these observations have been consistently replicated.
Subsequent studies have shown that HPA hyperactivity--as manifested by
hypersecretion of CRH; increased cortisol levels in plasma, urine and
cerebrospinal fluid; exaggerated cortisol responses to ACTH; and enlarged
pituitary and adrenal glands--occurs in individuals suffering from severe mood
disorders. Hypersecretion of CRH causing hypercortisolemia may be a result of
impaired feedback mechanisms resulting from GR abnormalities, such as decreased
receptor number or altered function. This view is supported by the demonstration
of GR abnormalities in postmortem studies of patients with severe mood disorders
(Webster et al., 2000). The dexamethasone suppression test (DST) is a measure of
the functional integrity of the GR-mediated negative feedback mechanism: The
cortisol-suppressing activity of the synthetic glucocorticoid dexamethasone is
an approximate indicator of GR status. Reports of cortisol non-suppression in
response to dexamethasone in both unipolar depressive and bipolar disorders do
indeed suggest a primary GR abnormality in these disorders (Zhou et al.,
1987).

Glucocorticoid Receptor Modulation

Pepin and colleagues (1989) were the first to demonstrate that treatments
used in mood disorders are able to affect GR function. These early in vitro
studies showed that tricyclic antidepressants had the ability to increase GR
mRNA in primary neuronal cultures, and subsequent in vivo studies have revealed
that this increase in GR mRNA is translated into an increase in receptor protein
and binding capacity. These changes have been reported following treatment with
the TCAs desipramine (Norpramin), imipramine (Tofranil) and amitriptyline
(Elavil) and the mood stabilizer lithium (Eskalith, Lithobid) (Peiffer et al.,
1991), and following electroconvulsive therapy (Przegalinski et al., 1993). It
is interesting, however, that neither citalopram (Celexa) (Seckl and Fink, 1992)
nor fluoxetine (Prozac) (Rossby et al., 1995) alters GR mRNA or GR binding
capacity, which suggests that the selective serotonin reuptake inhibitor class
of antidepressants may lack the ability to modulate GR expression and/or
function.

This evidence suggests that if indeed GR regulation is involved in the
therapeutic mechanism(s) of action of antidepressant drugs and mood stabilizers,
it is not a unitary mechanism. Antidepressant drugs that have the ability to
regulate GR expression and binding may, however, have greater therapeutic
efficacy in patients who have hypercortisolemia.

The development of a transgenic mouse line with reduced GR number has
provided further support for the hypothesis that altered GR function is central
to the pathogenesis of depressive disorders. As is common in humans with
depression, these mice exhibit HPA disturbances and cognitive deficits that are
partially normalized after antidepressant treatment (Pepin et al., 1992).
Furthermore, these transgenic mice exhibit attenuated 5-HT1A-mediated
hypothermia. A similar deficit is observed in drug-free people with depression,
particularly in those with depression of the melancholic type, a group strongly
associated with hypercortisolemia.